Treg deficiency-mediated TH 1 response causes human premature ovarian insufficiency through apoptosis and steroidogenesis dysfunction of granulosa cells.
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ABSTRACT:
SUBMITTER: Jiao X
PROVIDER: S-EPMC8214854 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Premature ovarian insufficiency (POI) is a heterogeneous and multifactorial disorder. In recent years, there has been an increasing interest in research on the pathogenesis and treatment of POI, owing to the implementation of the second-child policy in China. Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is an RNA-binding protein that can bind to specific RNA sequences. CPEB3 can bind to and affect the expression, cellular location, and stability of target RNAs. Cpeb3 is highly expressed in the ovary; however, its functions remain unknown. In this study, Cpeb3-mutant mice were used to characterize the physiological functions of CPEB3. Cpeb3-mutant female mice manifested signs of gradual loss of ovarian follicles, ovarian follicle development arrest, increased follicle atresia, and subfertility with a phenotype analogous to POI in women. Further analysis showed that granulosa cell proliferation was inhibited and apoptosis was markedly increased in Cpeb3-mutant ovaries. In addition, the expression of Gdf9, a potential target of CPEB3, was decreased in Cpeb3-mutant ovaries and oocytes. Altogether, these results reveal that CPEB3 is essential for ovarian follicle development and female fertility as it regulates the expression of Gdf9 in oocytes, disruption of which leads to impaired ovarian follicle development and POI.
| S-EPMC8688431 | biostudies-literature
Project description:ObjectivesPremature ovarian insufficiency (POI) refers to the decline and cessation of ovarian functions in women under 40 years of age. Melatonin (MT) acts as a protective for the ovary. This study elucidated the role of MT in autophagy of granulosa cells (GCs) in POI via modulating the phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway.MethodsThe expression levels of microRNA (miR)-15a-5p, signal transducer and activator of transcription 3 (Stat3), and relevant hormones in the clinically collected serum samples of POI patients and healthy controls were examined. Human ovarian granulosa-like tumor cells (KGN) underwent serum starvation (SS) treatment to induce POI cell models and then received MT treatment. The expression levels of miR-15a-5p, Stat3, p-PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR in KGN cells were tested via quantitative real-time polymerase chain reaction and Western blotting. KGN cell viability was assessed by MTT assay and the protein levels of autophagy-related markers Beclin-1, microtubule-associated protein light chain 3 II/I, and p62 were detected by Western blotting. The binding relation between miR-15a-5p and Stat3 was verified via the dual-luciferase reporter gene assay. Functional rescue experiments were performed to probe the underlying role of miR-15a-5p/Stat3/the PI3K-Akt-mTOR pathway in KGN cell autophagy.ResultsmiR-15a-5p was increased whilst Stat3 was decreased in the serum of POI patients and SS-induced KGN cells. MT inhibited miR-15a-5p and Stat3, activated the PI3K-Akt-mTOR pathway, and repressed cell autophagy in SS-induced KGN cells. miR-15a-5p targeted and repressed Stat3 expression. Upregulation of miR-15a-5p or downregulation of Stat3 or the PI3K-Akt-mTOR pathway promoted KGN cell autophagy.ConclusionMT suppressed miR-15a-5p and activated Stat3 and the PI3K-Akt-mTOR pathway, finally impeding SS-induced autophagy of GCs.
| S-EPMC9700896 | biostudies-literature
Project description:BackgroundThe ovarian environment of premature ovarian insufficiency (POI) patients exhibits immune dysregulation, which leads to excessive secretion of numerous proinflammatory cytokines that affect ovarian function. An abnormal level of macrophage polarization directly or indirectly inhibits the differentiation of ovarian granulosa cells and steroid hormone production, ultimately leading to POI. Resveratrol, as a health supplement, has been widely recognized for its safety. There is a substantial amount of evidence indicating that resveratrol and its analogs possess significant immune-regulatory functions. It has also been reported that resveratrol can effectively inhibit the progression of POI. However, the underlying immunological and molecular mechanisms through which resveratrol inhibits the progression of POI are still unclear.ResultsOur preliminary reports have shown that resveratrol-βcd, the beta-cyclodextrin complex of resveratrol, significantly enhances the stability of resveratrol. Resveratrol-βcd could regulate the dysfunctional immune status of macrophages and T cells in the tumor microenvironment. In this study, we treated busulfan and cyclophosphamide (B/C)-treated mice, which were used as a POI model, with resveratrol-βcd. After resveratrol-βcd treatment, the levels of IL-6 in the ovaries were significantly increased, and the progression of POI was suppressed. IL-6 activated granulosa cells (GCs) through soluble IL-6R (sIL-6R), promoting autophagy in GCs. Resveratrol-βcd and IL-6 had a synergistic effect on enhancing autophagy in GCs and promoting E2 secretion.ConclusionsWe partially elucidated the immune mechanism by which resveratrol inhibits the progression of POI and the autophagy-regulating function of GCs. This provides a theoretical basis for using resveratrol to prevent POI in future studies and clinical guidance.
| S-EPMC10789063 | biostudies-literature
Project description:This study investigated the effects of SOD2 (MnSOD)-deficiency-induced excessive oxidative stress on ovarian steroidogenesis in vivo and isolated and cultured granulosa cells using WT and Sod2+/- mice. Basal and 48 h eCG-stimulated plasma progesterone levels were decreased ~50% in female Sod2+/- mice, whereas plasma progesterone levels were decreased ~70% in Sod2+/- mice after sequential stimulation with eCG followed by hCG. Sod2+/- deficiency caused about 50% reduction in SOD2 activity in granulosa cells. SOD2-deficiency also caused a marked reduction in progestins and estradiol in isolated granulosa cells. qRT-PCR measurements indicated that the mRNA expression levels of StAR protein and steroidogenic enzymes are decreased in the ovaries of Sod2+/- mice. Further studies showed a defect in the movement of mobilized cytosolic cholesterol to mitochondria. The ovarian membrane from Sod2+/- mice showed higher susceptibility to lipid peroxidation. These data indicates that SOD2-deficiency induced oxidative stress inhibits ovarian granulosa cell steroidogenesis primarily by interfering with cholesterol transport to mitochondria and attenuating the expression of Star protein gene and key steroidogenic enzyme genes.
| S-EPMC8011630 | biostudies-literature
Project description:Primary ovarian insufficiency (POI), or premature ovarian failure, is defined as the cessation of ovarian function before the age of 40. An insufficient ovarian follicle pool derived from primordial germ cells (PGCs) is an important cause of POI. Although the Nanos gene family is known to be required for PGC development and maintenance in diverse model organisms, the relevance of this information to human biology is not yet clear. In this study, we screened the coding regions of the NANOS1, NANOS2 and NANOS3 genes in 100 Chinese POI patients and identified four variants in the coding regions of these three genes, including one synonymous variant in NANOS3, one missense variant in each of NANOS1 and NANOS2 and one potentially relevant mutation (c.457C>T; p.Arg153Trp, heterozygous) in NANOS3. We demonstrated that the p.Arg153Trp substitution decreases the stability of NANOS3, potentially resulting in a hypomorph. Furthermore, an investigation of the relationship between the number of PGCs and the dosage of NANOS3 in mouse models showed that the population of PGCs is controlled by the level of NANOS3 protein. Taken together, our results provide new insight into the properties of the NANOS3 protein and establish that NANOS3 mutation is one possible cause of POI.
| S-EPMC3824677 | biostudies-literature
Project description:BackgroundPremature ovarian insufficiency (POI) is one major cause of female infertility, minichromosome maintenance complex component 8 (MCM8) has been reported to be responsible for POI.MethodsWhole-exome sequencing was performed to identify the genetic variants of women with POI. Sanger sequencing was used to validate the variants in all the family members. Various bioinformatic software was used for the pathogenicity assessment. Reverse transcription polymerase chain reaction (RT-PCR), real-time quantitative PCR, and a chromosomal instability study induced by mitomycin C were performed to analyze the functional effects of the variant.ResultsA novel homozygous frameshift mutation (NM_032485.4:c.351_354delAAAG) of MCM8 gene was identified in the patients, segregated with POI in this family. This mutation is predicted to produce truncated MCM8 protein and to be pathogenic. Reverse transcription polymerase chain reaction revealed that the frameshift mutation led to a remarkably reduced level of MCM8 transcript products, and chromosomal instability study showed that the ability of mutant MCM8 to repair DNA breaks was impaired.ConclusionWe identified a novel homozygous frameshift mutation in the MCM8 gene in two affected sisters with POI, and functional analysis revealed that this mutation is pathogenic. Our findings enrich the MCM8 mutation spectrum and might help clinicians to make a precise diagnosis, thereby allowing better family planning and genetic counseling.
| S-EPMC7196458 | biostudies-literature
Project description:Primary ovarian insufficiency (POI) is defined as the loss of ovarian function before 40 years of age. It clinically manifests as amenorrhea, infertility, and signs of estrogen insufficiency. POI is frequently induced by chemotherapy. Gonadotoxic chemotherapy reagents damage granulosa cells, which are essential for follicular function and development. Our recently published studies demonstrated that intraovarian transplantation of human mesenchymal stem cells (hMSCs) can restore fertility in a chemotherapy-induced POI mouse model. However, the regenerative mechanism underlying the hMSC effect in POI mice is not fully understood. Here, we report that the hMSC secretome increased the proliferation of human granulosa cells (HGrC1). We showed by FACS analysis that treatment of HGrC1 cells with hMSC-conditioned media (hMSC CM) stimulates cellular proliferation. We also demonstrated that the expression of steroidogenic enzymes involved in the production of estrogen, CYP19A1 and StAR, are significantly elevated in hMSC CM-treated HGrC1 cells. Our data suggest that hMSC CM stimulates granulosa cell proliferation and function, which may explain the therapeutic effect of hMSCs in our chemotherapy-induced POI animal model. Our findings indicate that the hMSC secretome may be a novel treatment approach for restoring granulosa cell and ovarian function in patients with POI.
| S-EPMC7907146 | biostudies-literature
Project description:Ningxin-Tongyu-Zishen formula (NTZF) is a clinical experience formula for the treatment of premature ovarian insufficiency (POI) in traditional Chinese medicine (TCM), and the potential mechanism is unknown. For in vivo experiments, POI mouse models (C57BL/6 mice), were constructed by subcutaneous injection of D-galactose (D-gal, 200 mg/kg). After treatment of NTZF (10.14, 20.27, 40.54 g/kg;) or estradiol valerate (0.15 mg/kg), ovarian function, oxidative stress (OS) and protein expression of Sirt1/p53 were evaluated. For in vitro experiments, H2O2 (200 μM) was used to treat KGN to construct ovarian granulosa cells (OGCs) cell senescence model. Pretreatment with NTZF (1.06 mg/mL) or p53 inhibitor (Pifithrin-α, 1 μM) was performed before induction of senescence, and further evaluated the cell senescence, OS, mRNA and protein expression of Sirt1/p53. In vivo, NTZF improved ovarian function, alleviated OS and Sirt1/p53 signaling abnormalities in POI mice. In vitro experiments showed that NTZF reduced the level of OS and alleviated the senescence of H2O2-induced KGN. In addition, NTZF activated the protein expression of Sirt1, inhibited the mRNA transcription and protein expression of p53 and p21. Alleviating OGCs senescence and protecting ovarian function through Sirt1/p53 is one of the potential mechanisms of NTZF in the treatment of POI.
| S-EPMC10968698 | biostudies-literature
Project description:Premature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. This includes two genes, REC8 and HROB, not previously associated with autosomal recessive POI. REC8 encodes a component of the cohesin complex and HROB encodes a factor that recruits MCM8/9 for DNA damage repair. In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI. We also identified novel variants in MCM8, NUP107, STAG3 and HFM1 and a known variant in POF1B. Our study highlights the pivotal role of meiosis in ovarian function. We identify novel variants, consolidate the pathogenicity of variants previously considered of unknown significance, and propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis.
| S-EPMC8821714 | biostudies-literature
Project description:BackgroundPremature ovarian insufficiency (POI) patients are predisposed to metabolic disturbances, including in lipid metabolism and glucose metabolism, and metabolic disorders appear to be a prerequisite of the typical long-term complications of POI, such as cardiovascular diseases or osteoporosis. However, the metabolic changes underlying the development of POI and its subsequent complications are incompletely understood, and there are few studies characterizing the disturbed metabolome in POI patients. The aim of this study was to characterize the plasma metabolome in POI by using ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) metabolomics and to evaluate whether these disturbances identified in the plasma metabolome relate to ovarian reserve and have diagnostic value in POI.MethodsThis observational study recruited 30 POI patients and 30 age- and body mass index (BMI)-matched controls in the Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, from January 2018 to October 2020. Fasting venous blood was collected at 9:00 am on days 2-4 of the menstrual cycle and centrifuged for analysis. An untargeted quantitative metabolomic analysis was performed using UHPLC-MS/MS.ResultsOur study identified 48 upregulated and 21 downregulated positive metabolites, and 13 upregulated and 48 downregulated negative metabolites in the plasma of POI patients. The differentially regulated metabolites were involved in pathways such as caffeine metabolism and ubiquinone and other terpenoid-quinone biosynthesis. Six metabolites with an AUC value > 0.8, including arachidonoyl amide, 3-hydroxy-3-methylbutanoic acid, dihexyl nonanedioate, 18-HETE, cystine, and PG (16:0/18:1), were correlated with ovarian reserve and thus have the potential to be diagnostic biomarkers of POI.ConclusionThis UHPLC-MS/MS untargeted metabolomics study revealed differentially expressed metabolites in the plasma of patients with POI. The differential metabolites may not only be involved in the aetiology of POI but also contribute to its major complications. These findings offer a panoramic view of the plasma metabolite changes caused by POI, which may provide useful diagnostic and therapeutic clues for POI disease.
| S-EPMC9814329 | biostudies-literature